Parental diet and exposures are increasingly recognized as determinants of disease risk in offspring. Our contribution here has been to demonstrate that maternal supplementation with vitamins B2, B6, B12 and folate can suppress, while mild deficiency can promote, intestinal tumorigenesis in mouse offspring. We propose that modulating paternal diet will have similar effect on tumorigenesis in offspring. This issue is of importance because there may exist an opportunity to exploit a previously ignored means to lower the incidence of cancer in our society. Unlike the situation for expectant mothers, there are no dietary recommendations for men prior to conception and the incidence of mild deficiencies of vitamins B2, B6 and B12 remains high in the US (10-50%). Furthermore, despite the rarity of folate deficiency in the US, our data in mothers indicates that intakes above and beyond those considered adequate are required to maximally suppress intestinal tumorigenesis in offspring and that intakes considered 'adequate'are associated with elevated tumor incidence in offspring. Our long term goal is to minimize the risk of cancer in offspring by optimizing diet throughout the life cycle, including that of both parents. The objectives of this application are to determine whether paternal supplementation and depletion with vitamins B2, B6, B12 and folate can alter tumor incidence in offspring and to gain an understanding of the mechanisms involved. We hypothesize that supplemental quantities of vitamins B2, B6, B12 and folate in the paternal diet will suppress, while combined mild deficiency will promote tumorigenesis in offspring. Furthermore, that such effects will be associated with the prevention or promotion of deleterious promoter methylation and gene expression changes of members of the "Wnt" signaling pathway, a pathway that regulates cell division and death and is commonly disrupted in colorectal cancer. The primary Specific Aim of this proposal is to determine whether paternal supplementation of mild depletion of vitamins B2, B6, B12 and folate alters the incidence of intestinal tumors in offspring. A secondary aim is to determine whether observed changes in tumor incidence are associated with changes in the expression and methylation of Wnt pathway genes in the normal intestinal mucosa. This contribution is significant because understanding how B vitamins modulate the development of cancer in individuals and their offspring is essential for developing intelligently-constructed and effective measures that will utilize these vitamins in the prevention of cancer. PUBLIC HEALTH RELEVANCE: Maternal supplementation with vitamins B2, B6, B12 and folate dramatically suppresses intestinal cancer in the offspring of mice;however it is unknown whether modulating paternal intake has a similar effect. We aim to determine whether paternal B vitamin supplementation and depletion can alter the incidence of intestinal tumors in offspring. The acquisition of such knowledge is a cornerstone of developing intelligently-constructed dietary interventions for both parents aimed at reducing the incidence of cancer in offspring. Our study specifically pertains to colorectal cancer, a disease which kills approximately 60,000 people per year in the US, however the mechanisms involved may be shared amongst a variety of cancers.